This is an application for the K08 Mentored Clinical Scientist Research Career Development Award for Dr. Aras Mattis, a Gastrointestinal/Liver Pathology Postdoctoral Fellow at the University of California, San Francisco (UCSF). This K08 award will provide the core support necessary to establish Dr. Mattis as an independent researcher and to achieve the following career goals over the five year term of this award: 1) Become an expert in liver biology, development, and disease research especially as related to FLD, NASH, and liver metabolism, 2) increase his understanding of metabolic lipid pathways and analysis, and 3) master techniques in gene and microRNA array analysis. To achieve these goals, Dr. Mattis has developed a plan and assembled a multidisciplinary advisory team of scientists and physician-scientists specializing in liver biology, hepatic lipid metabolism, and cellular stress responses. With the rising North American obesity epidemic, secondary health problems associated with increased caloric intake have become common including FLD. While not all overweight individuals are at risk for FLD, the proportion is estimated to affect approximately 20% of the US population. For those that do develop FLD, over time one-tenth of those will go on to develop NASH resulting in fibrosis, cirrhosis, and increased risk for hepatocellular carcinoma (HCC). The long-term goal is to understand the molecular mechanisms leading to FLD and NASH including the genes that increase susceptibility to the disease as well as those that are protective. The objective for this project is to understand the role of microRNA 29a (miR-29a) in FLD and NASH. The hypothesis is that miR-29a is a central genetic switch that regulates hepatic lipid uptake, liver fibrosis, and inflammation. The specific experimental aims of this project are to 1) establish the role of miR-29a in hepatic lipid metabolism by determining the genes directly regulated by miR-29a, 2) establish that miR-29a over-expression in the liver is hepato-protective in the liver of mice challenged by a western-diet, and 3) evaluate the relative levels of miR-29a in a set of liver biopsies from patients with spectrum of fatty liver disease. This career development award and project will not only provide crucial training for Dr. Mattis, but this research project will also evaluate the role of miR-29a a a central regulator that might explain all the different characteristics of NASH pathology. This research takes both a basic biology approach using a model organism as well as a patient-oriented biopsy approach with direct relevance to human FLD and NASH. This project follows the mission of the NIH and more specifically of the NIDDK to support medical research on metabolic diseases, obesity, and nutritional disorders.